Folic Acid FIGURE 1 Chemical Structure of Folic

Folic Acid FIGURE 1: Chemical Structure of Folic Acid [8] By: Linda Kim Andrew Liu Milton Reisis PHM 226, Example Instructor: Dr. Jeffrey Henderson

WHAT IS FOLIC ACID? Folic acid = pteroylmonoglutamic acid, folacin, vitamin Bc, vitamin B 9 and Lactobacillus casei factor [8]. Folic acid is a water-soluble B-vitamin [8] MW = 441 k. Da Must be ingested in diet (cannot be synthesized by body)

WHY IS FOLIC ACID NEEDED? Formation of the coenzyme referred to as tetrahydrofolate (THF) [1] Essential for creating heme, the iron containing substance in haemoglobin [1] Proper formation of the brain, spinal cord, and nerve cells in the embryo. Closure of the neural tube in the fetus cannot be completed without it (Northrup H, 2000). Essential for synthesis of serine, methionine, ATP, GTP, thymidylate

ABSORPTION Natural food source (polyglutamate): conjugase in the small intestine’s lumen converts polyglutamates (low absorption) to monoglutamates for absorption [4] Monoglutamate is readily absorbed from the gut via energy-dependent, carrier-mediated mechanisms, involving membrane-associated folate-binding proteins [4]

DISTRIBUTION Tetrahydrofolate (THF) and its derivatives distribute to all body tissues [4] N 5 -methyl-THF is the major storage form of folate in the body (i. e. ~50% in liver) [4] N 5 -methyl-THF is highly bound to albumin [4]

METABOLISM Folate reduced to dihydrofolate (DHF) and then to tetrahydrofolate (THF) within cells, by dihydrofolate reductase (DHFR) and NADH [7] Addition of glutamate residues to THF in the cell keep it within the cell to form its active coenzyme in one-carbon metabolism reactions [7] 5 -methyl-THF is formed by the reduction of N 5, N 10 -methylene-FH 4 by N 5, N 10 -methylene-THF reductase [7] Normally, folate is excreted in the urine; folate is also excreted in the bile, if not reabsorbed [4]

TABLE 1: One-carbon pool: Sources and Recipients of Carbon [7] Source Form of THF produced Recipient Product Formate N 10 -Formyl Purine precursor Purine (C 2) Histidine N 5, N 10 -Methenyl Purine precursor Purine (C 8) Serine, Glycine, Formaldehyde N 5, N 10 -Methylene d. UMP Glycine d. TMP Serine Reduction of N 5, N 10 -methylene. THF N 5 -Methyl Vitamin-B 12 Methyl-B 12

HOW DOES FOLIC ACID WORK? Folic acid is converted to its active coenzyme form, THF, which behaves as a donor or receiver of a one carbon entity in different oxidation states (formyl, methylene, or methyl)

FIGURE 2: FOLATE MECHANISM OF ACTION [9]

FIGURE 3: MECHANISM OF ACTION – EXAMPLE [9]

FIGURE 4: MECHANISM OF ACTION – EXAMPLE [2]

Sources of Folic Acid Cereals (100 -400 mcg), dark green vegetables (120 -160 mcg), citrus fruits (50 -100 mcg) [10] Folic acid may also be found in supplements and multivitamin combinations sold at pharmacies

Folate Deficiency

Causes of Folate Deficiency Decreased intake (diet, malabsorption) Increased need (pregnancy) Also, consider decreased availability (antifolate drugs etc. )

WHAT ARE NEURAL TUBE DEFECTS (NTDs)? l. The neural tube forms in the embryo and then closes (between the 2 nd and 4 th week of gestation) l. A neural tube defect occurs when the neural tube fails to close properly l. The two most common NTDs are anencephaly and spina bifida

What is Spina Bifida? Occurs when the two sides of the spine fail to close and protect the spinal cord There are two forms of spina bifida: 1) Spina bifida occulta (mildest form) 2) Spina bifida manifesta which includes two types of spina bifida: meningocele and myelomeningocele

What is Spina Bifida? Source: http: //www. surgical-tutor. org. uk/default-home. htm? system/hnep/neural_tube. htm~right

What Causes Spina Bifida? Largely unknown Some evidence suggests that genes may be involved. (Northrup H et al, 2000) A high fever during pregnancy or epileptic women who have taken the drug valproic acid to control seizures may have an increased risk of having a baby with spina bifida. (Lewis DP et al, 1998)

How Can NTDs be Prevented? All women of childbearing age should receive 0. 4 mg (400 micrograms) of folic acid daily prior to conception of planned or unplanned pregnancies and continue thru 1 st trimester Women with a history of NTD and should receive daily supplementation of 4 mg (4000 micrograms) of folic acid starting three months prior to conception and continuing thru the 1 st trimester

References [1] Adams, S. L. 2003. Biochemical Functions of Folic Acid, http: //www. i 2 k. com/~suzanne/page 25. htm , accessed [1] Adams, S. L. 2003. Biochemical Functions of Folic Acid, http: //www. i 2 k. com/~suzanne/page 25. htm, accessed January 2004. [2] Angstadt , C. N. 1997. Purine and Pyrimidine Metabolism, [2] Angstadt, C. N. 1997. Purine and Pyrimidine Metabolism, http: //www. mcphu. edu/netbiochem/pupyr/pp. htm#Syn%20 TMP, accessed January 2004. [3] Castillo, E. S. 1991. Folic Acid, http: //www. inchem. org/documents/pims/pharm/folicaci. htm#Part. Title: 3. %20 PHYSICOCHEMICAL%20 PROPERTIES, accessed January 2004. [4] Expert Group on Vitamins and Minerals. 2002. Review of Folic Acid, http: //www. foodstandards. gov. uk/multimedia/pdfs/evm 0018 p. pdf, accessed January 2004. [5] Fenech M. 2001. The role of folic acid and vitamin B 12 in genomic stability of human cells. Mutat Res 475(1 -2): 5767 [6] Larsen, H. R. 2000. Folic Acid: Don’t Be Without It!, http: // vvv. com/healthnews/folic_acid. html, accessed January [6] Larsen, H. R. 2000. Folic Acid: Don’t Be Without It!, http: //vvv. com/healthnews/folic_acid. html 2004. [7] Marks, D. B. , Marks, A. D. , and Smith, C. M. 1996. Basic Medical Biochemistry: A Clinical Approach. , Williams and Wilkins, Maryland, pp 613 -632. [8] No author. 2002. Folic Acid, http: //www. chm. bris. ac. uk/webprojects 2002/schnepp/folic. html , accessed January [8] No author. 2002. Folic Acid, http: //www. chm. bris. ac. uk/webprojects 2002/schnepp/folic. html, accessed January 2004. [9] No author. 2002. Main Folate Metabolism Pathways, http: //www. humboldt. edu/~rap 1/Bioch. Supp/Pathway. Diagrams/Fol. Met. Path. gif, accessed January 2004. [10] No author. 2003. CERHR: Folic Acid, http: //cerhr. niehs. nih. gov/genpub/topics/folic_acid-ccae. html , accessed [10] No author. 2003. CERHR: Folic Acid, http: //cerhr. niehs. nih. gov/genpub/topics/folic_acid-ccae. html, accessed January 2004. [11] Wolfson , D. 2001. Pharmaceutical Drugs Deplete Folic Acid, [11] Wolfson, D. 2001. Pharmaceutical Drugs Deplete Folic Acid, http: //www. newhope. com/nutritionsciencenews/NSN_backs/Sep_01/folic. cfm, accessed January 2004.

References *For NTD section All. Refer Health – Caring for your Well Being: http: //health. allrefer. com/health/folic-acid-folate-info. html All. Refer Health – Caring for your Well Being: http: //health. allrefer. com/health/folic-acid-folate-info. html Champel V et al. Should folic acid be given to women treated with valproic acid and/or carbamazepine? Folic acid Champel V et al. Should folic acid be given to women treated with valproic acid and/or and pregnancy in epilepsy. Rev Neurol. 1999 Mar; 155(3): 220 -4. and pregnancy in epilepsy. Rev Neurol Geisel J. Folic acid and neural tube defects in pregnancy: a review. J Perinat Neonatal Nurs. 2003 Oct-Nov; 17(4): Geisel J. Folic acid and neural tube defects in pregnancy: a review 268 -79. Lewis DP et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998 Jul-Aug; 32(7 -8): 802 -17. drugs, contraceptives, smoking, and folate. Ann Pharmacother Lewis DP et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part II: Lewis DP et al. Improvement with folic acid. Ann Pharmacother. 1998 Sep; 32(9): 947 -61. Review. Improvement with folic acid. Ann Pharmacother MEDLINEplus – Spina Bifida: http: //www. nlm. nih. gov/medlineplus/spinabifida. html MEDLINEplus – Spina MEDLINEplus – Folic Acid: http: //www. nlm. nih. gov/medlineplus/folicacid. html MEDLINEplus – Folic Acid: http: // Northrup H et al. Spina bifida and other neural tube defects. . Curr Probl Northrup H et al. Spina Probl Pediatr. 2000 Nov-Dec; 30(10): 313 -32. Pregnancy and Nutrition - Spina Bifida and Folic Acid: http: //www. bchealthguide. org/healthfiles/hfile 38 c. stm Pregnancy and Nutrition - Spina Bifida and Folic Acid: Ray JG et al. Association of neural tube defects and folic acid food fortification in Canada. Lancet. 2002 Dec 2128; 360(9350): 2047 -8. Spina Bifida Association of America – Facts about Spina Bifida: http: //www. sbaa. org/html/sbaa_facts. html Spina Bifida Association of America – Facts about Spina Surgical-tutor. org. uk – a free online surgical resource: http: //www. surgical-tutor. org. uk/default. Surgicalhome. htm? system/hnep/neural_tube. htm~right The Arc – Prevention of Neural Tube Defects: http: // www. thearc. org/faqs/folicqa. html The Arc – Prevention of Neural Tube Defects: http: //www. thearc. org/faqs/folicqa. html Wald NJ. Folic Acid and the Prevention of Neural-Tube Defects. N. N Engl J Med. 2004 Jan 8; 350(2): 101 -3. Wald NJ. Folic Acid and the Prevention of Neural-Tube Engl J Med. 2004 Jan 8; 350(2): 101 -3.

References *For anemia section Briggs, Gerald G. , Freeman, Roger K. , Yaffe , Sumner J. Folic Acid. A Reference Guide to Fetal and Neonatal Briggs, Gerald G. , Freeman, Roger K. , Yaffe, Sumner J. Folic Acid. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 5 th Ed. Lippincott , Williams & Wilkins: Philadelphia, PA, USA. 1998. Ed. Lippincott, Williams & Wilkins: Philadelphia, PA, USA. 1998. pp. 456 - 467 Cotran, Kumar, Collins et al. Red Cells and Bleeding Disorders. Pathologic Basis of Disease. W. B. Saunders Company: Philadelphia, PA. 1999. pp. 604 -627 Eichner, E. R. and Hillman, R. S. The evolution of anemia in alcoholic patients. Am. J. Med. , 1971, 50: 218 -232 Eichner, E. R. and Hillman, R. S. Effect of alcohol on serum folate level. J. Clin. Invest. , 1973, 52: 584 -591 Eichner, E. R. and Hillman, R. S. Effect of alcohol on serum folate level. J. Clin Folic Acid. USP DI Vol. 1 Drug Information for the Health Care Professional. 23 rd Ed. Micromedex : Colorado, Ed. Micromedex: Colorado, USA. 2003. pp. 1376 -1378 Hillman, Robert S. Chapter 54 Hematopoietic Agents. Goodman & Gilman’s Pharmacological Basis of Therapeutics. 10 th Ed. Hardman, Joel G. , Limbird , Lee E. , Goodman Gilman, Alfred, eds. The Mcgraw-Hill Ed. Hardman, Joel G. , Limbird, Lee E. , Goodman Gilman, Alfred, eds. The Companies, Inc. : USA. 2001. pp. 1503 -1514 Herbert, V. , Tisman , G. , Le-Teng-Go, and Brenner, L. The d. U suppression test using 125 -I-UDR to define Herbert, V. , Tisman, G. , Lebiochemical megaloblastosis. Br. J. Haematol. , 1973. 24: 713 -723 biochemical megaloblastosis. Br. J. Teresi, Mary E. , Kailis, Stanley G. , Berbatis, Constantine G. Iron Deficiency and Megaloblastic Anemias. . Teresi, Mary E. , Kailis Textbook of Therapeutics Drug and Disease Management. 6 th Ed. Herfindal , Eric T. , Gourley, Dick K. , eds. Ed. Herfindal, Eric T. , Williams & Wilkins: Baltimore, Maryland, USA. 1996. pp. 201– 220 Tropical Sprue. The Merck Manual Second Home Edition. Merck & Co. Inc. : Whitehouse Station, NJ, USA, 2004. http: //www. merck. com/mrkshared/mmanual_home 2/sec 09/ch 125/ch 125 d. jsp